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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
  • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings
  • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention is concerned with new sulphonamidoalkyl-cycloalkane compounds, processes for the preparation thereof and pharmaceutical compositions containing them.
• the new sulphonamides according to the present invention are compounds of the general formula: ##STR2## wherein R 1 and R 2 , which can be the same or different, are hydrogen or halogen atoms or C 1 -C 6 -alkyl, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl radicals or, when R 1 and R 2 are alkyl radicals ortho to one another, R 1 and R 2 , together with the two carbon atoms to which they are attached, form a saturated or unsaturated C 5 -C 7 -alkylene ring, R 3 is a hydrogen atom, an alkyl radical containing up to 6 carbon atoms, an acyl radical, a phenylalkyl or phenylalkenyl radical, the phenyl moiety of which can be substituted by halogen, alkyl or trifluoromethyl
• the new compounds of general formula (I) show an excellent antagonistic action towards thromboxane A 2 , as well as against prostaglandin endoperoxides and have an activity which is superior to that of the compounds known from the prior art. They inhibit the aggregation of blood platelets and prevent the constriction of the smooth musculature, as well as bronchoconstriction. Furthermore, they are valuable medicaments for the treatment of pathological changes of the kidney function.
• R 1 , R 2 , R 3 or A are lower alkyl radicals, then there are to be understood thereunder unbranched and branched radicals containing up to 6 carbon atoms, the methyl, butyl and n-hexyl radicals being preferred.
• R 1 and R 2 together form a ring, then a six-membered ring is preferred. Especially preferred in this sense is the case in which R 1 and R 2 , together with the ring to which they are attached, form an ⁇ - or ⁇ -naphthyl or a tetrahydronaphthyl radical which can possibly be substituted by the groups defined in the case of R 1 and especially by halogen atoms.
• halogen atoms are fluorine, chlorine or bromine, chlorine and bromine being preferred.
• the tetrazolyl radical is especially the 1H-tetrazol-5-yl radical.
• phenylalkyl radicals R 3 there can be used those with up to 3 carbon atoms in the alkyl moiety, in which case the phenyl radical is substituted especially by halogen atoms.
• phenylalkenyl radicals R 3 are to be understood radicals in which the alkenylene moiety contains 3 or 4 carbon atoms.
• the phenyl moiety can possibly be substituted by halogen atoms.
• the acyl radicals R 3 are derived from aliphatic carboxylic acids containing 2 to 6 carbon atoms and from arylaliphatic, preferably phenylalkyl and aromatic carboxylic acids.
• R 3 can be an acetyl, formyl or benzoyl radical.
• C preferably has the meaning --(CH 2 ) m --, in which m is 0, 1, 2 or 3.
• B is preferably a cyclohexylidene radical in which the substituents A and C can be in the cis or trans position to one another and the substitution is preferably in the 1,4- or 1,3-position.
• A is defined as being an alkyl radical containing up to 6 carbon atoms or as an alkyl radical containing up to 6 carbon atoms which carries a terminal hydroxyl function.
• A can be a carboxyl group, a tetrazolyl radical or a C 1 -C 5 -alkyl radical with a terminal carboxyl or tetrazolyl radical.
• the just defined alkyl radicals can, in each case, be substituted by a function containing an oxygen atom, i.e. by a hydroxyl or oxo group.
• A can preferably be a carboxy-C 1 -C 5 -alkoxy or tetrazolyl-C 1 -C 5 -alkoxy radical but especially an oxyacetic acid radical or a tetrazolylmethoxy radical.
• A is an unbranched or branched saturated alkyl radical and especially one of the general formula:
• p is a number of from 1 to 6.
• A is an unbranched or branched saturated alkyl radical which carries a terminal carboxyl function or a tetrazolyl radical and especially one of the general formulae:
• p is a number of from 1 to 6.
• A is an unbranched or branched saturated alkyl radical which carries a terminal hydroxyl group and especially one of the general formula:
• p is a number of from 1 to 6.
• A is a --D--R 4 radical, wherein D is a carbonyl group --CO-- and
• R 4 is an unbranched or branched saturated alkyl radical containing up to 5 carbon atoms and especially one of the general formula:
• p is a number of from 2 to 6;
• R 4 is an unbranched or branched saturated alkyl radical containing up to 5 carbon atoms which carries a terminal hydroxyl group and especially one of the general formula:
• p is a number of from 3 to 6;
• R 4 is an unbranched or branched alkyl radical with a terminal carboxyl or tetrazolyl radical and especially one of the general formula:
• p is a number of from 3 to 6 but preferably of from 4 to 6.
• A is a D--R 4 radical in which D is a --CHOH-- group and R 4 has the above-given meaning and especially one of the following general formulae:
• A is a --O--(CH 2 ) q --COOH radical, wherein q is a number of from 1 to 5.
• R 1 or R 2 a hydrogen, chlorine or bromine atom or a methyl, n-butyl and n-hexyl, trifluoromethyl, cyano or aminocarbonyl radical.
• R 1 and R 2 is a hydrogen atom or the mono-substituted derivatives, preferably in the 4-position of the phenyl ring
• R 3 hydrogen, a methyl, n-butyl or n-hexyl radical; acetyl, n-hexanoyl or benzoyl; benzyl; phenethyl or cinnamyl, the phenyl moieties of which can be substituted by halogen, especially by chloride.
• A an ethyl, butyl or hexyl radical or also a carboxyl or 1H-tetrazol-5-yl radical or an alkyl radical terminally substituted by one of these two groups.
• A carboxyl, 1H-tetrazol-5-yl, carboxymethyl, carboxypropyl or carboxybutyl and the 1H-tetrazol-5-yl analogues thereof.
• Especially preferred groups A as given under point 4a) include, for example, acetyl, butyryl and hexanoyl, of type 4b) hydroxybutanoyl and of type 4c) 3-carboxypropanoyl.
• A is an alkyl radical terminally substituted by a hydroxyl group
• 2-hydroxyethyl, 4-hydroxybutyl and 6-hydroxyhexyl radicals there are especially preferred the 2-hydroxyethyl, 4-hydroxybutyl and 6-hydroxyhexyl radicals.
• the present invention also includes the salts, esters and amides thereof and when A contains not only a carboxyl group but also a hydroxyl group, the "internal esters", i.e. the lactones, are also included.
• oxyalkylcarboxylic acids are especially preferred the oxyacetic acids and by the tetrazolyl-C 1 -C 5 -alkoxy compounds those with a (1H-tetrazol-5-yl)-methoxy radical.
• esters those are preferred with lower monohydroxy alcohols, for example methanol or ethanol, or with polyhydroxy alcohols, for example glycerol, but there are also included those alcohols which contain other functional groups, for example ethanolamine.
• a compound of general formula (I) contains an asymmetric carbon atom
• the present invention includes not only the pure optical isomers but also the mixtures/racemates thereof. If the molecule contains double bonds, then the present invention includes the pure E (entussi, trans) and Z (zusammen, cis) isomers, as well as mixtures thereof. With regard to the substituents in the cyclohexyl ring, there are included not only the cis but also the trans isomers.
• the new compounds of general formula (I) according to the present invention can be prepared by one of the following methods:
• A contains a hydroxyl group
• a compound (V) which, instead of the hydroxyl group, contains a carboxy group or an ester function or possibly both. Subsequent to the reaction between (IV) and (V), this group is reduced to the hydroxyl function.
• R 3 is other than a hydrogen atom.
• the halides As reactive derivatives of the sulphonic acids (III), there are especially preferred the halides, as well as the esters.
• the reaction of the sulphonic acid halides with compounds of general formula (II) advantageously takes place with the addition of an acid-binding agent, for example an alkali metal acetate, sodium hydrogen carbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate.
• an acid-binding agent for example an alkali metal acetate, sodium hydrogen carbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate.
• organic bases for example pyridine or triethylamine, in which case, as inert solvent, there can be used, for example, diethyl ether, benzene, methylene chloride, dioxane or an excess of the tertiary amine.
• the amines of general formula (II) can also be used in the form of their acid-addition salts, for
• reaction medium there can be used, for example, water, aqueous ethanol or aqueous dioxane.
• X is a halogen atom, for example chlorine or bromine, but preferably those in which X is an arylsulphonyloxy radical.
• alkylation agents there are preferably used arylsulphonic acid alkyl esters, a method, the use of which for sulphonic acid amides, is described, for example, by Klamann et al., Monatshefte fur Chemie, 83, 871/1952.
• the reaction takes place in an alkaline medium, a preferred reaction medium being a hot, concentrated solution of sodium carbonate.
• a polar solvent for example dimethylformamide.
• R 3 group is to be introduced, then this takes place by reaction of a compound (I), in which R 3 is a hydrogen atom, with an acid halide when R 3 is an acyl radical.
• a halide chloride or bromide of general formula (VI), working being under the above-described conditions.
• the acylation of the sulphonamide takes place in an inert solvent, for example diethyl ether or methylene chloride, and as acid-bonding agent there is preferably used an organic base, for example pyridine or triethylamine.
• an inert solvent for example diethyl ether or methylene chloride
• an organic base for example pyridine or triethylamine.
• the reduction with complex hydrides, for example with sodium borohydride, protic solvents, for example water, (aqueous) alcohols or aqueous dioxane, thereby being used as reaction medium.
• protic solvents for example water, (aqueous) alcohols or aqueous dioxane
• the reduction can also be carried out with complex aluminium hydrides, for example lithium aluminium hydride, in which case aprotic solvents, for example diethyl ether, tetrahydrofuran or dioxane, here serve as reaction medium.
• the carbonyl reduction can take place with catalytically activated hydrogen, for example with hydrogen/Raney nickel, or by reaction with nickel-aluminium alloy in aqueous alkali.
• reducing agents for example complex hydrides, such as lithium aluminium hydride, or boran adducts, for example BH 3 .THF.
• the reduction can also take place advantageously by the reduction of a derivative of the carboxylic acid, for example of a mixed anhydride of the carboxylic acid and of a carbonic acid hemiester.
• complex boron hydrides for example sodium borohydride, in a protic solvent.
• carboxylic acids suitable for the reduction are, for example, also the esters thereof which can be reacted to give primary alcohols by methods known from the literature.
• preferred reducing agents are complex aluminium hydrides, for example lithium aluminium hydride.
• carboxyl function is to be reduced without an oxo group simultaneously present in A also being reduced, then the latter is to be protected temporarily, for example by ketalisation.
• hydroxyketones can also be prepared by reducing not only the keto group but also the carboxyl function, in which case there are obtained diols which are also within the scope of the present invention, and subsequently the secondary hydroxyl function is selectively oxidised to the keto function.
• etherification of cycloalkanols of general formula (VII) with halocarboxylic acids takes place in the presence of alcoholate-forming agents, for example sodium hydride, but preferably n-butyl lithium under phase transfer conditions, i.e. in a mixture of an aqueous solution of an alkali, a suitable organic solvent, for example methylene chloride, and in the presence of a quaternary ammonium salt, for example tetra-n-butylammonium bromide.
• alcoholate-forming agents for example sodium hydride, but preferably n-butyl lithium under phase transfer conditions, i.e. in a mixture of an aqueous solution of an alkali, a suitable organic solvent, for example methylene chloride, and in the presence of a quaternary ammonium salt, for example tetra-n-butylammonium bromide.
• the salts of hydrazoic acid which, in the process according to the present invention, are reacted with nitriles can be, for example, alkali metal salts, for example lithium azide, sodium azide and potassium azide, alkaline earth metal salts, for example magnesium azide, calcium azide or strontium azide, or metal salts, for example aluminium azide, tin azide, zinc azide or titanium azide, ammonium azide or salts with organic bases, for example aniline azide and the like.
• alkali metal salts for example lithium azide, sodium azide and potassium azide
• alkaline earth metal salts for example magnesium azide, calcium azide or strontium azide
• metal salts for example aluminium azide, tin azide, zinc azide or titanium azide, ammonium azide or salts with organic bases, for example aniline azide and the like.
• the pure azides it is expedient not to use the pure azides but rather to react them in mixtures with, for example, ammonium chloride or an alkylammonium chloride or also in combination with a Lewis acid, for example aluminium chloride, tin chloride, zinc chloride or titanium tetrachloride.
• a Lewis acid for example aluminium chloride, tin chloride, zinc chloride or titanium tetrachloride.
• hydrazoic acid or salts thereof, as well as the Lewis acid or ammonium chloride or alkylammonium chloride which are used in combination with the alkali metal azides are used in 1 to 10 molar excess, referred to the nitriles.
• carboxylic acids For the preparation of salts of pharmacologically acceptable organic or inorganic bases, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids can be reacted with the appropriate bases. Mixtures of the carboxylic acids with an appropriate alkali metal carbonate or hydrogen carbonate can also be used.
• the amines of general formula (II), in which B is a cyclohexylidene radical, required as starting materials for the preparation of compounds of general formula (I) are advantageously prepared by the hydrogenation of the aromatic analogues of the general formula: ##STR10##
• the compounds of general formula (IV) and (VII) and the precursors thereof are known from European Patent Specifications Nos. 0,031,954, 0,221,344 and 0,239,907.
• the hydrogenation takes place in the presence of metal catalysts, for example platinum, ruthenium or rhodium, possibly in the form of their oxides, for example ruthenium dioxide, at an elevated pressure, for example of from 50 to 150 bar, and at an elevated temperature, for example of from 70° to 100° C.
• solvents there are preferably used lower aliphatic carboxylic acids, for example acetic acid, or of particular alcohols, for example ethanol.
• A is a --CO--R 4 radical
• the carbonyl compound is first reduced to the carbinol and the aromatic nucleus is then subsequently hydrogenated under gentle conditions, for example at about 50° C., in the presence of platinum dioxide or ruthenium dioxide in ethanol.
• the carbinol group is thereafter again oxidised to the oxo group.
• the compounds of general formula (I) are mixed in known manner with appropriate pharmaceutical carrier materials, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.
• the compounds of general formula (I) can be administered orally or parenterally in liquid or solid form.
• injection medium it is preferred to use water which contains the stabilising agents, solubilising agents and/or buffers usual in the case of injection solutions.
• Additives of this type include, for example tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbitan anhydrides.
• Solid carrier materials can be, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
• Compositions which are suitable for oral administration can, if desired, contain flavouring and sweetening materials.
• the dosage administered depends upon the age, state of health and weight of the recipient, the extent of the disease, the nature of further treatments possibly carried out simultaneously, the frequency of the treatments and the nature of the desired action.
• the daily dose of the active compounds is from 0.1 to 50 mg./kg. of body weight. Normally, 0.5 to 40 and preferably 1.0 to 20 mg./kg./day in one or more administrations per day are effective in order to obtain the desired results.
• preferred compounds according to the present invention also include the following:
• Example 4 This is obtained analogously to Example 4 from 4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-cyclohexylacetic acid and 5-amino-1,2,3,4-tetrazole; m.p. 216° C. (decomp.) after recrystallisation from ethanol.
• a mixture of 2.5 g. (7 mMol) of the nitrile obtained according to b), 70 ml. 1-methylpyrrolidone, 1.49 g. (10 mMol) triethylammonium chloride and 1.40 g. (20 mMol) sodium azide is stirred for 6 hours at 150° C.
• the 1-methylpyrrolidone is then distilled off in a vacuum and the residue is dissolved in a dilute aqueous solution of sodium hydroxide and extracted three times with diethyl ether.
• the aqueous solution is acidified with 6N hydrochloric acid and then extracted four times with ethyl acetate.
• the extract is dried with anhydrous sodium sulphate and evaporated. Yield 2.1 g. (75% of theory); m.p. 122°-123° C.
• Platelet-rich human blood plasma was treated with 3.2% citrate at a volume ratio of 1:9 to inhibit clotting.
• a selective thromboxane mimetic, U46619 which is a stable analog of the prostaglandin endoperoxide PGH 2 , as described by Coleman et al., Brit. J. Pharmocol. 68, 127p (1980) was obtained from Upjohn & Co., Kalamazoo, Mich.
• the test protocol was that described by Born and Cross, J. Physiol. 168, 178 (1963) with the degree of aggregation measured using a 4-channel aggregometer (Profiler, Bio/Data Co.).
• the compounds of this invention, Examples 2.1, 4(cis) 4(trans), 6 ad 7 were diluted in saline, at final concentrations of 10-4 to 10-9 M. Saline was used as a control. Measurements were made for a period of five minutes, After addition of the tromboxane mimetic. From the data obtained, an inhibitory concentration IC 50 was calculated using standard methods. The results are shown in Table 1.
• mice Male NMRI mice, having a body weight of approximately 25 g, were separated into groups of 5. Representative examples of the compounds of this invention listed in part (a) were suspended in 1% methyl cellulose and administered to the animals by gastric intubation in amounts providing 1/mg/kg and 25/mg/kg of the antagonist. Four hours after intubation, a previously determined lethal dose of U46619 (800-1000 ug/kg) was injected into the tail vein of each animals. The survival rates for each group of mice was determined after 24 hours. The results are shown in Table 1 and indicate correlation with the IC 50 measured in vitro.

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